OBJECTIVES: Korea's Act on the Registration and Evaluation of Chemicals (K-REACH) was enacted for the protection of human health and the environment in 2015. Considering that about 2000 new substances are introduced annually across the globe, the extent of animal testing requirement could be overwhelming unless regulators and companies work proactively to institute and enforce global best practices to replace, reduce or refine animal use. In this review, the way to reduce the animal use for K-REACH is discussed. METHODS: Background of the enforcement of the K-REACH and its details was reviewed along with the papers and regulatory documents regarding the limitation of animal experiments and its alternatives in order to discuss the regulatory adoption of alternative tests. RESULTS: Depending on the tonnage of the chemical used, the data required ranges from acute and other short-term studies for a single exposure route to testing via multiple exposure routes and costly, longer-term studies such as a full two-generation reproducibility toxicity. The European Registration, Evaluation, Authorization and Restriction of Chemicals regulation provides for mandatory sharing of vertebrate test data to avoid unnecessary duplication of animal use and test costs, and obligation to revise data requirements and test guidelines “as soon as possible” after relevant, validated replacement, reduction or refinement (3R) methods become available. Furthermore, the Organization for Economic Cooperation and Development actively accepts alternative animal tests and 3R to chemical toxicity tests. CONCLUSIONS: Alternative tests which are more ethical and efficient than animal experiments should be widely used to assess the toxicity of chemicals for K-REACH registration. The relevant regulatory agencies will have to make efforts to actively adopt and uptake new alternative tests and 3R to K-REACH.
Animal Experimentation ; Animals ; Humans ; Organisation for Economic Co-Operation and Development ; Practice Guidelines as Topic* ; Toxicity Tests ; Vertebrates

PURPOSE: Rapid growth of prescription drug expenditures is a problem in South Korea. The objective of this study was to assess the contributions of four variables (therapeutic choice, drug-mix, original use, and price changes) to increases in drug expenditures paid by the National Health Insurance (NHI) in Korea. MATERIALS AND METHODS: A retrospective cohort study was conducted between January 1, 2008 and June 30, 2012 utilizing data from the NHI Claims Database of the Health Insurance Review and Assessment Service. The number of target drug types for final analysis was 13959. To analyze the growth rates of drug expenditures, this study used Fisher ideal index and the Laspeyres and Paasche indexes. RESULTS: With the exception of 2012, therapeutic choice contributed to about 40-60% of the increase in drug expenditures every year, while drug-mix contributed to another 30-40%. CONCLUSION: The rapid growth in prescription drug expenditure was found to be largely due to drug-mix and therapeutic choice over time. Original use had little impact on drug spending.
Cohort Studies ; Health Expenditures/*statistics & numerical data ; Humans ; National Health Programs/*economics ; Prescription Drugs/*economics ; Republic of Korea ; Retrospective Studies

Primary signet ring cell carcinoma of the urinary bladder is a relatively rare histological variant of mucus-producing adenocarcinoma usually of poor prognosis. We report two cases of primary bladder signet ring carcinoma. The first patient underwent a radical cystectomy with ileal conduit (pT3bN1M0), radiotherapy, and chemotherapy (M-VAC regimen) and subsequently expired 37 months after surgery. The other was initially diagnosed with peritoneal metastasis from the primary bladder signet ring cell carcinoma and was treated with partial cystectomy (pT3bNOM1). Postoperative adjuvant therapy was not done because of patient's refusal.
Adenocarcinoma ; Carcinoma, Signet Ring Cell ; Cystectomy ; Disulfiram ; Humans ; Neoplasm Metastasis ; Prognosis ; Urinary Bladder ; Urinary Diversion

PURPOSE: The role of PM10 in the development of allergic diseases remains controversial among epidemiological studies, partly due to the inability to control for spatial variations in large-scale risk factors. This study aims to investigate spatial correspondence between the level of PM10 and allergic diseases at the sub-district level in Seoul, Korea, in order to evaluate whether the impact of PM10 is observable and spatially varies across the subdistricts. METHODS: PM10 measurements at 25 monitoring stations in the city were interpolated to 424 sub-districts where annual inpatient and outpatient count data for 3 types of allergic diseases (atopic dermatitis, asthma, and allergic rhinitis) were collected. We estimated multiple ordinary least square regression models to examine the association of the PM10 level with each of the allergic diseases, controlling for various sub-district level covariates. Geographically weighted regression (GWR) models were conducted to evaluate how the impact of PM10 varies across the sub-districts. RESULTS: PM10 was found to be a significant predictor of atopic dermatitis patient count (P<0.01), with greater association when spatially interpolated at the sub-district level. No significant effect of PM10 was observed on allergic rhinitis and asthma when socioeconomic factors were controlled for. GWR models revealed spatial variation of PM10 effects on atopic dermatitis across the sub-districts in Seoul. The relationship of PM10 levels to atopic dermatitis patient counts is found to be significant only in the Gangbuk region (P<0.01), along with other covariates including average land value, poverty rate, level of education and apartment rate (P<0.01). CONCLUSIONS: Our findings imply that PM10 effects on allergic diseases might not be consistent throughout Seoul. GIS-based spatial modeling techniques could play a role in evaluating spatial variation of air pollution impacts on allergic diseases at the sub-district level, which could provide valuable guidelines for environmental and public health policymakers.
Air Pollution ; Asthma ; Dermatitis ; Dermatitis, Atopic ; Education ; Environmental Policy* ; Epidemiologic Studies ; Humans ; Inpatients ; Korea ; Outpatients ; Particulate Matter ; Poverty ; Public Health ; Rhinitis ; Risk Factors ; Seoul* ; Socioeconomic Factors ; Spatial Analysis

Menkes disease (also known as kinky hair disease) is an X-linked recessive neurodegenerative disorder caused by diverse mutations in a copper-transport gene, ATP7A. Affected patients are characterized by kinky hair, hypotonia, and generalized myoclonic seizures. Here, we report a case of Menkes disease in which the patient presented with progressive hypotonia and intractable seizures. A 4-month-old male infant visited our pediatric clinic for focal seizures with blinking eyes. He was generally hypotonic and suffered from malnutrition. The focal seizures became more frequent, and the patient became intractable to anti-seizure medications. An electroencephalogram (EEG) indicated diffuse cerebral dysfunction with focal seizure, and a brain magnetic resonance imaging (MRI) showed tortuous and ectatic intracranial arteries, as well as several ischemic lesions. A genetic analysis was performed, and a c.2473_2474del (p.Leu825fsX1) of the ATP7A gene was detected.
Arteries ; Blinking ; Brain ; Electroencephalography ; Epilepsy* ; Hair ; Humans ; Infant ; Magnetic Resonance Imaging ; Male ; Malnutrition ; Menkes Kinky Hair Syndrome* ; Muscle Hypotonia ; Neurodegenerative Diseases ; Seizures

Objectives: Early pharmacologic intervention is considered necessary for improving the prognosis in patients with first-episode schizophrenia (FES). However, few nationwide population-based studies have focused on early medication adherence. We investigated the status of early adherence to antipsychotics and the effect of early adherence on later clinical outcomes in FES. Methods: We used data from the South Korean Health Insurance Review Agency database (2009-2021). We selected 28,931 patients with FES who had a prescription record of at least one antipsychotic medication within 180 days after their diagnosis. We measured early medication adherence using the medication possession ratio (MPR) and compared demographic characteristics and results of psychiatric hospitalization between the adherence group (0.6≤MPR<1.1) and the non-adherence group (MPR<0.6). Results: The average early medication adherence was 0.82 by MPR, and the non-adherence group accounted for 15.6% of all subjects. From 1 to 2 years after diagnosis, the adherence group showed a higher number of psychiatric hospitalizations per hospitalized patient but a shorter duration than the non-adherence group. Additionally, the proportion of patients who experienced psychiatric hospitalizations was smaller in the adherence group. Conclusion In patients with FES, early medication adherence is associated with lower rates of psychiatric hospitalization and shorter hospitalization durations.

PURPOSE: To decide the optimal treatment for breast cancer patients with locoregional recurrence (LRR), it is important to determine which group has the highest risk of subsequent distant metastasis (DM). We aimed to investigate the factors associated with DM in patients with LRR. METHODS: We reviewed the data of 208 patients with LRR as the first event after primary surgery for breast cancer at our institution between 1997 and 2010, to identify significant factors associated with DM. Subsequently, Kaplan-Meier curves and the Cox regression method were used to analyze the correlation between clinical factors and survival. RESULTS: DM occurred in 33.2% (68/208) of LRR patients. The median DM-free interval was 23 months. Some clinical factors were associated with DM in univariate analysis, including the type of primary surgery (p=0.026), tumor size (p=0.005), nodal status (p=0.011), and administration of initial adjuvant chemotherapy (p=0.001). In addition, regional rather than local recurrence and a disease-free interval (DFI; duration between primary surgery and LRR) < or =30 months were also significant (p<0.001 for both). However, only a shorter DFI reached significance in multiple logistic regression analysis. Cox regression analysis of DM-free survival showed that both a shorter DFI and regional recurrence were significant factors with hazard ratios of 2.1 (95% confidence interval [CI], 1.21-3.65) and 1.85 (95% CI, 1.04-3.28), respectively. CONCLUSION: DFI was the most important factor associated with subsequent DM in patients with LRR as a first event of failure.
Breast Neoplasms* ; Chemotherapy, Adjuvant ; Humans ; Logistic Models ; Neoplasm Metastasis* ; Neoplasm Recurrence, Local ; Prognosis ; Recurrence* ; Risk Factors*

Among various vaccines against Actinobacillus pleuropneumoniae, subunit vaccines using recombinant proteins of ApxI, ApxII, and ApxIII as vaccine antigens have shown good efficacy in terms of safety and protection. Therefore, subunit vaccines are being applied worldwide and the development of new subunit vaccines is actively being conducted. To evaluate the efficacy of the subunit vaccines, it is important to measure immune responses to each Apx toxin separately. However, the cross-reactivity of antibodies makes it difficult to measure specific immune reactivity to each toxin. In the present study, specific antigen regions among the toxins were identified and cloned to solve this problem. The antigenicity of each recombinant protein was demonstrated by Western blot. Using the recombinant proteins, we developed enzyme-linked immunosorbent assay (ELISA) methods that can detect specific immune responses to each Apx toxin in laboratory guinea pigs. We suggest that the ELISA method developed in this study can be an important tool in the evaluation of vaccine efficiency and vaccine development.
Actinobacillus pleuropneumoniae ; Actinobacillus ; Animals ; Antibodies ; Blotting, Western ; Clone Cells ; Enzyme-Linked Immunosorbent Assay ; Guinea Pigs ; Methods ; Recombinant Proteins ; Vaccines ; Vaccines, Subunit

BACKGROUND AND PURPOSE: We investigated predictors of institutionalization in patients with Alzheimer's disease (AD) in South Korea. METHODS: In total, 2,470 patients with AD aged 74.5±7.8 years (mean±standard deviation, 68.1% females) were enrolled from November 2005 to December 2013. The dates of institutionalization were identified from the public Long-Term-Care Insurance program in January 2014. We used a Cox proportional-hazards model to identify predictors for future institutionalization among characteristics at the time of diagnosis in 2,470 AD patients. A similar Cox proportional-hazards model was also used to investigate predictors among variables that reflected longitudinal changes in clinical variables before institutionalization in 816 patients who underwent follow-up testing. RESULTS: A lower Mini Mental State Examination score [hazard ratio (HR)=0.95, 95% confidence interval (CI)=0.92–0.97] and higher scores for the Clinical Dementia Rating and Neuro-Psychiatric Inventory (HR=1.01, 95% CI=1.00–1.01) at baseline were independent predictors of institutionalization. The relationship of patients with their main caregivers, presence of the apolipoprotein E e4 allele, and medication at baseline were not significantly associated with the rate of institutionalization. In models with variables that exhibited longitudinal changes, larger annual change in Clinical Dementia Rating Sum of Boxes score (HR=1.15, 95% CI=1.06–1.23) and higher medication possession ratio of antipsychotics (HR=1.89, 95% CI=1.20–2.97) predicted earlier institutionalization. CONCLUSIONS: This study shows that among Korean patients with AD, lower cognitive ability, higher dementia severity, more-severe behavioral symptoms at baseline, more-rapid decline in dementia severity, and more-frequent use of antipsychotics are independent predictors of earlier institutionalization.
Alleles ; Alzheimer Disease* ; Antipsychotic Agents ; Apolipoproteins ; Behavioral Symptoms ; Caregivers ; Dementia ; Diagnosis ; Follow-Up Studies ; Humans ; Institutionalization* ; Insurance ; Korea*

BACKGROUND: Idiopathic pulmonary fibrosis involves irreversible alveolar destruction. Although alveolar epithelial type II cells are key functional participants within the lung parenchyma, how epithelial cells are affected upon bleomycin (BLM) exposure remains unknown. In this study, we determined whether BLM could induce cell cycle arrest via regulation of Schlafen (SLFN) family genes, a group of cell cycle regulators known to mediate growth-inhibitory responses and apoptosis in alveolar epithelial type II cells. METHODS: Mouse AE II cell line MLE-12 were exposed to 1–10 µg/mL BLM and 0.01–100 µM baicalein (Bai), a G1/G2 cell cycle inhibitor, for 24 hours. Cell viability and levels of pro-inflammatory cytokines were analyzed by MTT and enzyme-linked immunosorbent assay, respectively. Apoptosis-related gene expression was evaluated by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Cellular morphology was determined after DAPI and Hoechst 33258 staining. To verify cell cycle arrest, propidium iodide (PI) staining was performed for MLE-12 after exposure to BLM. RESULTS: BLM decreased the proliferation of MLE-12 cells. However, it significantly increased expression levels of interleukin 6, tumor necrosis factor α, and transforming growth factor β1. Based on Hoechst 33258 staining, BLM induced condensation of nuclear and fragmentation. Based on DAPI and PI staining, BLM significantly increased the size of nuclei and induced G2/M phase cell cycle arrest. Results of qRT-PCR analysis revealed that BLM increased mRNA levels of BAX but decreased those of Bcl2. In addition, BLM/Bai increased mRNA levels of p53, p21, SLFN1, 2, 4 of Schlafen family. CONCLUSION: BLM exposure affects pulmonary epithelial type II cells, resulting in decreased proliferation possibly through apoptotic and cell cycle arrest associated signaling.
Animals ; Apoptosis ; Bisbenzimidazole ; Bleomycin ; Cell Cycle Checkpoints ; Cell Cycle ; Cell Line ; Cell Survival ; Cytokines ; Enzyme-Linked Immunosorbent Assay ; Epithelial Cells ; Gene Expression ; Genes, vif ; Humans ; Idiopathic Pulmonary Fibrosis ; Interleukin-6 ; Lung ; Mice ; Propidium ; RNA, Messenger ; Transforming Growth Factors ; Tumor Necrosis Factor-alpha